Compounds active on the cardiovascular system

ABSTRACT

Compounds of the formula ##STR1## (wherein Ar, R, R 1 , R 2 , R 3 , R 4 , R 5 , m and n have the meanings given in the description), their preparation and pharmaceutical compositions containing them. 
     The compounds of formula I are active on the cardiovascular system as antivasospastics, antiangina agents, antihypertensives and vasodilators.

This application is a continuation of U.S. Ser. No. 07/386,236, filedJul. 28, 1987, now abandoned.

The present invention relates to compounds active on the cardiovascularsystem; more particularly, it relates to compounds having adihydropyridine nucleus, pharmaceutically acceptable salts thereof,processes for preparing them and pharmaceutical compositions containingthem.

Compounds having calcium-antagonist properties and 4-aryldihydropyridinestructure are known; their typical representative is4-(2-nitrophenyl)-2,6-dimethyl-3,5-dimethoxcarbonyl-1,4-dihydropyridineknown as Nifepidine (Merck Index 10th Ed., No. 6374) of the formula##STR2## Beta-blocking drugs are also known and widely used in therapyfor treating cardiovascular diseases. In most cases these drugs arestructurally related to 3-aryloxy-2-hydroxy-propan-amines.

Examples of beta-blockers most commonly used in therapy, mainly asantihypertensives, include Alprenolol (Merck Index, X ed., No. 304),Atenolol (Merck Index, X ed., No. 868), Carteolol (Merck Index, X ed.,No. 1850), Metoprolol (Merck Index, X ed., No. 6027), Nadolol (MerckIndex, X ed., No. 6195), Oxprenol (Merck Index, X ed., No. 6820),Pindolol (Merck Index, X ed., No. 7317), Propanolol (Merck Index, X ed.,No. 7740), and Timolol (Merck Index, X ed., No. 9284).

Furthermore, some compounds have been described wherein the3-aryloxy-2-hydroxy-propanamine moiety of beta-blockers is linked atdifferent positions of the 4-aryl-dihydropyridine moiety endowed withcalcium-antagonist activity.

Baldwin J. J. et al., J. Med. Chem., 1981, 24 628-631 disclosescompounds wherein the beta-blocker chain is linked to the aryl moiety of4-aryl-dihydropyridine at position 4, but these compounds resultedscarcely active; European Patent Application No. 179386 (Bayer A. G.)describes compounds wherein the beta-blocker chain is linked at thecarboxy group at position 3 of the 4-aryl-dihydropyridine.

Now we have found a novel class of compounds wherein both a typicalbeta-blocker structure and a calcium-antagonist moiety are suitablyinterconnected and show a remarkable antihypertensives activity.

It is therefore an object of this invention to provide a compound of theformula: ##STR3## wherein

Ar is a mono- or dicyclo aromatic or heteroaromatic ring system havingfrom 5 to 10 atoms in the aromatic nucleus optionally substituted by oneor more substituents selected from halogen, hydroxy, C₁ -C₅ alkyl, C₂-C₅ alkenyl, C₁ -C₃ alkoxy, alkoxyalkyl having from 1 to 5 carbon atomsboth in the alkyl and in the alkoxy moiety and an optional unsaturationin the chain, phenoxy, phenylalkoxy, aminocarbonylalkyl having from 1 to3 carbon atoms in the alkyl moiety, cyano, carboxy, carbamoylalkyl,aminocarboxy, amino, mono- and di-alkylamino where the nitrogen atom maybe a part of a ring;

R and R₁, the same or different, are hydrogen or C₁ -C₃ alkyl;

R₂ is a straight or branched C₁ -C₇ alkyl or a straight or branched C₂-C₇ alkenyl optionally substituted by aryl, additionally R₂ may be X-R₇where X is CO, CS or SO₂ and R₇ is an alkyl or an alkoxyalkyl havingfrom 1 to 5 carbon atoms both in the alkyl and the alkoxy moiety,hydroxy, C₁ -C₃ alkoxy, mono- or di-alkylamino having from 1 to 5 carbonatoms in the alkyl moiety, or C₁ -C₅ alkylthio;

R₃ is cyano, amino or C₁ -C₃ alkyl optionally substituted by fluorineatoms;

R₄ and R₆, the same or different, are alkyl or alkoxyalkyl having from 1to 5 carbon atoms both in the alkyl and alkoxy moiety;

R₅ is a ring selected from phenyl, naphthyl, tetrahydro-naphthyl andindanyl, wherein said ring may be substituted by one or moresubstituents selected from halogen, hydroxy, alkyl, alkenyl, alkoxy,alkenyloxy, alkoxyalkyl, alkanoyl, trifluoromethyl, amino, nitro,carbamoyl, cyano, alkylthio, carbamoylalkyl and alkanoylamino having upto 6 carbon atoms in the alkyl moiety;

m and n, the same or different, are 1, 2 or 3; and the salts thereofwith organic or inorganic pharmaceutically acceptable acids.

The compounds of formula I have at least two asymmetric carbon atoms andcan therefore exist as stereoisomers.

Another object of this invention is to provide the compounds of formulaI both as stereoisomeric mixtures and as single stereoisomers.

The single stereoisomers are obtained by stereoselective synthesis or byseparation from the stereoisomeric mixture according to such knowntechniques as fractional crystallization, chromatography and resolutionby means of salification or preparation of derivatives with opticallyactive compounds.

The salts of the compounds of this invention with pharmaceuticallyacceptable organic and inorganic acids are prepared according toconventional methods.

Examples of pharmaceutically acceptable acids are hydrochloric,hydrobromic, phosphoric, sulfuric, lactic, succinic, tartaric, acetic,salicyclic, citric, benzoic, p-hydroxybenzoic, naphthalene-2-sulfonic,adipic and pimelic acid.

The compounds of formula I and their pharmaceutically acceptable saltsare active on the cardiovascular system as antivasospastics, antianginaagents, antihypertensives and vasodilators.

Unless otherwise stated, when used in connection with R, R₁, R₂, R₃, R₄,R₅, R₆, R₇ and Ar, alkyl means a straight or branched alkyl having,preferably, from 1 to 6 carbon atoms (typical examples being methyl,ethyl, n-propyl, 1-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl andn-hexyl); the alkyl moiety of alkoxy and alkoxyalkyl is intended to havethe meaning cited above for alkyl; aryl and aromatic or heteroaromaticsystem mean an aromatic or heteroaromatic nucleus having 5(heteroaromatic), 6, 9, 10 or 12 members and the heteroaromatic nucleusmay have from 1 to 3 heteroatoms selected from oxygen, sulfur andnitrogen (typical examples being furyl, pyrrolyl, isoxazolyl,1,2,5-triazolyl, oxazolyl, phenyl, pyridyl, indenyl, indolyl, naphthyl,benzofuranyl, isobenzofuranyl, quinolyl, diphenyl and phenylipyridyl);alkenyl means a branched or straight alkenyl radical having from 2 to 7carbon atoms and at least one unsaturation (typical examples beingvinyl, allyl, 2,2-dimethylvinyl, and 1-butadienyl); alkanoyl means aresidue of a straight or branched carboxylic acid having 1 to 5 carbonatoms (typical examples being formyl, aceyl, butyroyl and isobutyroyl).

A preferred group of compounds of formula I includes those compoundswherein Ar has the same meaning as the aryl group in knownbeta-blockers.

Preferred meanings of Ar comprise phenyl, naphthyl, isobenzofuranyl,benzofuranyl, 3,4-dihydrocarbostyryl, benzopyranyl, tetrahydronaphthyl,carbazolyl, indeny, indolyl and 1,2,5-thiadiazolyl, optionallysubstituted.

Examples of possible substituents comprise one or more fluorine,chlorine, bromine, acetyl, allyl, carbamoylmethyl, butyroylamino,cyclohexyl, cyano, hydroxy, butyroyl, acetylamino, methoxycarbonyl,methoxyethyl, methoxy, allyloxy, cyclopentyl, cyclopropyl, morpholine,ethyl and isobutyroyl.

Specific examples of preferred substituted aryls comprise2-methoxyphenyl, 2-allyloxyphenyl, 2-cyanophenyl, 2-methylphenyl,2-allylphenyl, 4-carbamoylmethylphenyl, 4-hydroxyphenyl,4-morpholino-1,2,5-thiadiazol-3-yl, indol-4-yl and3,4-dihydro-1-(H)-carbostyryl-5-yl.

Another group of preferred compounds includes those compounds wherein R₅is a substituted phenyl and more particularly 3-nitrophenyl,2-nitrophenyl, 2-chlorophenyl, 2-trifluoromethyl-phenyl, and2,3-dichlorophenyl.

A third group of preferred compounds includes those compounds wherein Rand R₁, the same or different, are hydrogen or methyl.

A fourth group of preferred compounds comprises those compounds whereinR₃ is methyl or trifluoromethyl.

Finally, among the compounds of general formula I a group of mostpreferred compounds comprises the compounds wherein

Ar is selected from 2-methoxyphenyl, 2-allyloxyphenyl, 2-cyanophenyl,2-methylphenyl, 2-allylphenyl, 4-carbamoylmethylphenyl, 4-hydroxyphenyl,4-morpholino-1,2,5-thiadiazol-3-yl, indol-4-yl and3,4-dihydro-1(H)-carbostyryl-5-yl;

R and R₁, the same or different, are hydrogen or methyl;

R₂ has the meanings mentioned above in connection with formula I;

R₃ is methyl or trifluoromethyl;

R₄ and R₆ have the meanings mentioned above in connection with formulaI;

R₅ is phenyl substituted by one or more substituents selected fromnitro, trifluoromethyl and halogen;

X is a carbonyl or sulfonic group.

R₇ is methyl, ethyl, isopropyl, phenyl, dimethylamino, diethylamino,methoxy or ethoxy.

A further object of this invention is to provide a process for preparinga compound of formula I comprising (i) the condensation of the R₂ --NH--group of a diamine of the formula ##STR4## wherein R, R₁, and m have themeanings mentioned above in connection with formula I and R₂ is a memberselected from alkyl and alkenyl, wherein both members, straight orbranched, have from 1 to 7 carbon atoms and are optionally substitutedby an aryl group;

with a 2-alkylen-4-aryl-dihydropyridine and (ii) the introduction of a3-aryloxy-2-hydroxy-propyl radical on the primary amino group of (II).

Both steps can be performed according to several procedures and step(ii) may also precede step (i).

In the following description of the synthesis method R, R₁, R₃, R₄, R₅,R₆, Ar, m and n have the meanings already mentioned above in relation toformula I, R2 has the meanings already mentioned above in relation toformula II.

Before performing step (i), the primary amino group of diamine II ispreferably protected according to conventional techniques. Examples ofsuitable protective groups comprise benzyl, benzyloxycarbonyl,ter.butyloxycarbonyl and phthalimido group.

Step (i) affords, after condensation of a2-alkylen-4-aryl-dihydropyridine compound with a protected diamine (II)and subsequent removal of the protecting group, a compound of formula##STR5##

Step (ii) involves condensation of the compound (III) with an epoxide(IV) or with a compound of formula or (V) ##STR6## wherein X is halogen,alkyl or arylsulfonyloxy, to afford a compound of formula I.

A preferred way of performing step (i) comprises the condensation of aprotected diamine (II) with a 2-alkylene-4-aryl-dihydropyridine compoundof formula ##STR7## wherein Y is a leaving group.

Examples of preferred leaving groups comprise chlorine, bromine, iodine,alkylsulfonyloxy, and arylsulfonyloxy. Typical examples of preferredleaving groups are methanesulfonyloxy, benzenesulfonyloxy andp-toluenesulfonyloxy.

The condensation of compound (IV) with a protected diamine (II) isperformed in an inert solvent and in the presence of a base.

After preferred way of performing step (i) comprises the condensation ofa protected diamine (II) with a 2-alkylen-4-aryl-dihydropyridinecompound of the formula ##STR8##

The condensation of compound (VII) with a protected diamine (II) isperformed in an inert solvent, optionally in the presence of adehydrating agent, and subsequent reduction. This reduction ispreferably carried out by catalytic hydrogenolysis or with reducingagents, such as sodium boron hydride and sodium cyano hydride.

When step (ii) is carried out before step (i), the diamine (II) isoptionally protected on the secondary amino group (R₂ --NH--), theoptionally protected diamine (II) is then reacted with a compound offormula (IV) or (V) to give, after removal of the possible protectivegroup, a compound of the formula ##STR9## and finally the compound(VIII), is reached with a compound of formula (VI) or (VII).

Protection and removal of the protective group are carried out asdescribed above.

The condensation reaction of the optionally protected diamine (II) witha compound of formula (IV) or (V) is also performed as described abovein connection with the reaction of compound (III) with compounds (IV) or(V).

Even the reaction of compounds (VIII) with compound (VI) or (VII) iscarried out as described above.

Another way for performing step (ii) before step (i) comprises preparinga compound of the formula ##STR10## wherein

R₂ ' is hydrogen or a member selected from alkyl and alkenyl whereinboth members, straight or branched, have from 1 to 7 carbon atoms andare optionally substituted by an aryl group; and

R₈ is a protective group; by reacting an amide of the formula ##STR11##with a compound of formula (IV) or (V) to give a compound of the formula##STR12## which is then protected by a protective agent and reduced toafford a compound of formula (IX).

The preferred meaning of R₈ is trifluoromethyl.

Reduction is preferably carried out with hydrides, such as lithiumaluminum hydride, lithium boron hydride, cobalt boron hydride andborane.

Another way of performing step (i) comprises the reaction of a compoundof formula (IX) with a compound of formula (VI) or (VII) to give acompound of the formula ##STR13##

This reaction is carried out as described above in relation to thepreparation of compound (III).

When R₂ ' is a member selected from alkyl and alkenyl, wherein bothmembers, straight or branched, have from 1 to 7 carbon atoms and areoptionally substituted by an aryl group, the compound of formula I canbe easily prepared by simple removal of the protective group fromcompound (XII) according to conventional techniques, such as, atreatment with an acid.

When R'₂ is hydrogen, the compound of formula I is prepared byalkylation or acylation of compound (XII) and subsequent removal of theprotective group.

The alkylation is carried out in an inert solvent and in the presence ofa base with an alkylating agent of the formula

    R.sub.2 --X'                                               (XIII)

where X' is chlorine or bromine; or with methyl sulfate.

Reacting a compound of formula (XII), wherein R₂ ' is hydrogen, withsuitable reactive derivatives of a carboxylic or a sulfonic acids, suchas chlorides and anhydrides, or of carbonic acids, such aschlorocarbonates and chlorocarbamates; with isocyanates orisothiocyanates and subsequent removal of the protective group accordingto conventional methods, the compounds of formula I wherein R₂ is X--R₇are obtained.

The condensation reaction is carried out in a suitable inert solvent,optionally in the presence of an organic or inorganic base as acidacceptor, at a temperature of from 0° C. to the reflux temperature ofthe reaction mixture.

Examples of suitable solvents comprise hydrocarbons, such as toluene andcyclohexane; ethers, such as tetrahydrofuran and dioxane; chlorinatedhydrocarbons, such as dichloromethane, chloroform andtetrachloroethylene.

Examples of suitable bases comprise inorganic bases, such as alkali andalkaline-earth metals hydroxydes; bicarbonates and carbonates; andorganic base, such as triethylamine and pyridine, which can also act asa solvent. Preferred bases are sodium and potassium hydroxides,bicarbonates and carbonates.

The process of this invention contemplates also the protection of theamino group via formation of a heterocyclic ring, such as the conversionof compound (XI) to an oxazolidine compound of the formula ##STR14##wherein R₉ is C₁ -C₆ alkyl or phenyl.

Compounds of formula (XIV) are prepared by reacting a compound (XI),wherein the nitrogen atom linked to R₂ ' is protected, or a compound(XI) where R₂ ' is R₂, with an aldehyde of the formula

    R.sub.9 --CHO                                              (XV)

At the end of the process, the oxazolidine ring is opened by treatmentwith acids and the hydroxy group is thus restored.

The compounds of formula I of this invention have at least two asymmetrycenters which are marked by an asterisk.

The asymmetric synthesis for preparing diastereoselectively thecompounds of formula I can be performed, for example, via opticallyactive intermediate compounds of formula (III), (IV), (V), (VI), (VII)or (IX).

The compounds of formula (VI) and (VII) are known, for example, fromEuropean Patent Applications 109 009 and 212 340 or can be easilyprepared according to the Hantszch method by reacting the compounds offormula R₅ --CHO (XVI) and R₃ --C(NH₂)═CH--COOR₄ (XVII) and a keto esterof formula R₆ OOC--CH₂ --CO--(CH₂)_(n-1) --R₁₀ (XVIII) wherein R₁₀ is--CH₂ --Y or --CHO or any other similar group, such as --CH₂ OH.

The compounds of formula I proved be useful in the treatment ofcardiovascular pathologies as anti-vasospastics, antiangina agents,antihypertensives and vasodilators.

The pharmacological activity of the compounds of this invention has beentested both in vitro and in vivo (Example 16).

The compounds of formula I are endowed with a remarkable calciumantagonist and beta blocking action and are useful in producingantihypertensive effects with concomitant reduction of heart rate,contrary to known calcium-antagonists in which the hypotensive effect isaccompained by tachycardia.

In addition to a remarkable action on the cardiovascular system, thecompounds of formula I show interesting properties which make themparticularly suitable for use in the pharmaceutical field.

Contrary to the known drugs having a dihydropyridine structure, thecompounds of formula I have a considerable chemical and physicalstability.

A still further object of the present invention is to provide apharmaceutical composition containing a compound of formula I or apharmaceutically acceptable salt thereof together with one or more solidor liquid, organic or inorganic pharmaceutical excipients, such asdiluents, preservatives, humectants, dyes, flavours and the like.

The pharmaceutical compositions of the present invention may beadministered as solid dosage forms, such as tablets, pills, capsules,granules and suppositories, or an liquid dosage forms, such as syrups,suspensions, emulsions and solutions suitable for oral or parenteraladministration, or also as dosage forms suitable for transdermaladministration, such as wax plasters.

The compounds of the present invention may also be compounded in slowreleasing dosage forms.

The preparation of the pharmaceutical compositions of the presentinvention is carried out according to conventional techniques.

The doses of the compound of formula I will vary according to severalfactors, such as the specific activity of the single compound of formulaI, the therapy and the individual patient response as well as theselected administration route.

Generally the amount of the compound of formula I to be administeredwill be in the range of from 0.1 mg to 200 mg per day in one or morerepeated doses.

For the purpose of better illustrating the present invention, thefollowing examples are now given.

EXAMPLE 1 Preparation of ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methyloropyl)aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate(Compound 1)

A mixture of ethyl1,4-dihydro-2-formyl-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicaboxylate(5.0 g; 13 mmoles), and ofN-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropylamine(3.65 g; 13 mmoles) in 95% ethanol (70 ml) is stirred for one hour atroom temperature.

After cooling to 0°-5° C., water (31.8 ml), acetic acid (10.9 ml),sodium acetate (3.45 g) and finally sodium boron hydride (2.55 g; 70mmoles) are added. The mixture is left for four hours at roomtemperature. After solvent evaporation, water is added to the residuewhich is basified with dilute ammonia and extracted with methylenechlorie.

The organic phase is dried over sodium sulfate and after evaporation ofthe solvent the residue is purified by chromatography on a silica gelcolumn (230-400 mesh), eluting with methylene chloride and increasingamounts of ethanol up to a 95:5 ratio.

Ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methyloropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylateis obtained as 1:1 mixture of the two diastereomer pairs (thin layerchromatography--eluent ethyl acetate:NH₄ OH=99.1).

The two diastereomeric pairs had Rf=0.22 and Rf=0.17, respectively.

¹ H-NMR diastereomeric mixture--free base (300 MHz, CDCl₃) delta (ppm);1.18 (6H, 4s); 1,22 (6H, 2t); 2.40 (6H, s); 2.59 (2, m); 3.84 (3H, 2s);3.93 (2H, m); 5.09 (1H, s); 7.35 (1H, 2t); 7.62 (1H, d); 7.98 (1H, d);8.12 (1H bs).

The signal at 7.35 ppm is splitted because of the presence of twodiastereoisomers and become simple in the spectra of the two purediatereooisomers.

The two diastereoisomers were separated by chromatography on a silicagel column (230-400 mesh) eluting with ethylacetate; NH₄ OH=99:1.

The less polar product is salified with a solution of hydrochloric acidin ether to give a crystalline hydrochloride salt melting at 116°-118°C. (ethyl acetate).

EXAMPLE 2 Preparation of methyl1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-(2-oxo-ethyl)-3,5-pyridinedicarboxilate

A solution of methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate(34.6 g; 0.10 mmoles) and N,N-dimethylformamide dimethylacetale (14.7 g;0.12 mmoles) in dimethylformamide is heated to reflux under nitrogenatmosphere for 16 hours.

The solvent is evaporated and the crude product is extracted withtoluene and water. The organic phase is separated and, after drying oversodium sulfate, the solvent is evaporated.

Methyl1,4-dihydro-2-(2-N,N-dimethylamino-ethyl)-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylateis obtained which is directly hydrolyized without any furtherpurification.

A solution of this compound (6 g; 15 mmoles) in acetone (60 ml) istreated for one hour under nitrogen atmosphere and at room temperaturewith hydrochloric acid 6N (6.96 ml).

The cold solution is evaporated and some water is added; the solution isfiltered, the filtrate is diluted with water and extracted withmethylene chloride.

After drying over sodium sulfate, the solvent is evaporated obtainedmethyl1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-(2-oxo-ethyl)-3,5-pyridinedicarboxilate,chromatographically pure oil (thin layer chromatography--eluentmethylene chloride:methanol:NH₄ OH=94.5:5:0.5).

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 374(m+1)⁺.

EXAMPLE 3 Preparation of methyl1,4-dihydro-6-methyl-2-N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)propylamino)-2-methylpropyl)-aminoethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Operating in a way similar to that described in example 1 but using1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-(2-oxo-ethyl)-3,5-pyrinedicarboxylateas the starting aldehyde and carrying out the reduction reaction indioxane for 12 hours methyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminoethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylateis obtained, yellow chromatographycally pure oil (thin layerchromatography--eluent methylene chloride:methanol:NH₄ OH=94.5:5:0.5.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 1.20 (6H, 4s); 2.34 (3H, 2s);2.44 (3H, 2s); 2.52 (2H, bd); 3.62 (6H, m); 3.83 (3H, s); 4.05 (2H, m);4.25 (1H, m); 5.06 (1H, s); 7.35 (1H, 2t); 7.61 (1H, bd); 7.95 (1H, dd);8.10 (1H, bs).

Working in a similar way, from the levo rotatory enantiomer ofN-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropylamine(prepared as described in example 8) methyl1,4-dihydro-6-methyl-(-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)aminoethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylateis obtained as a mixture of two diatereoisomers.

EXAMPLE 4 Preparation of N-methyl-3-amino-3-methyl-butyramide

A mixture of methyl 3-amino-3-methyl-butyrate hydrochloride (10.5 g;62.6 mmoles) and methyl amine (33% solution in ethanol; 55 ml) isrefluxed for 18 hours. The solvent is evaporated, the crude is dissolvedin methylene chloride (100 ml) and washed with a saturate aqueoussolution of sodium chloride (10 ml). After drying over sodium sulphateand evaporation of the solvent to dryness,N-methyl-3-amino-3-methyl-butyramide is obtained; chromatographicallypure colorless oil (T.L.C., eluent--methylene chloride:methanol:NH₄OH=80:15:1)

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 131(M+1)⁺ ; 114.

¹ H-NMR (60 MHz, CDCl₃): delta (ppm): 1.2 (6H, s); 2.2 (2H,s); 2.8 (3H,s).

EXAMPLE 5 Preparation of(-)-N-methyl-2-(2-hydroxy-3-(2-methoxy-phenoxy)propylamino)-2-methyl-propionamide

a) A mixture of 1,2-epoxy-3-(2-methoxyphenoxy)-propane (14 g; 0.077moles) and N-methyl-2-amino-2-methylpropionamide (9.0 g; 0.077 moles) isabsolute ethanol (90 ml) is heated at 80° C. for two hours.

After evaporation of the solvent, the crude product is dissolved inethyl acetate (100 ml) and a solution of ethyl acetate/concentrate HCl85:15 is added dropwise, while cooling with ice, till pH issubstantially acid.

The oily phase which precipitates by acidification is separated anddissolved in water (100 ml).

The so obtained solution is brought to pH 5-6 with a dilute sodiumhydroxide solution and is extracted twice with ethyl acetate (50 ml).The aqueous phase is separated and made alkaline with potassiumbicarbonate; the solution is then saturated with sodium chloride andextracted with ethyl acetate (3×80 ml).

The organic phase is dried over sodium sulfate and filtered and thesolvent is evaporated.N-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methyl-propionamideis thus obtained as a chromatographycally pure colourless oil (thinlayer chromatography--eluent, chloroform:methanol:NH₄ OH=79:15:1).

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 1.35 (6H, s); 1.70 (2H, bs;exchange with D₂ O); 2.72 (2H, m); 2.78 (3H, d); 3.85 (3H, s); 3.98 (1H,dd); 4.05 (1H, m); 4.15 (1H, dd); 6.90-7.02 (4H, m); 7.35 (1H, bq).

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 297(M+1)⁺ ; 238.

b) A mixture ofN-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)propylamino)-2-methyl-propionamide(146 g; 0.49 moles) and (+)-camphosulfonic acid (114 g; 0.49 moles) inethyl acetate (1.5 l) is heated to reflux until completely dissolved.

The solution is cooled to room temperature and after 10 hours isfiltered.

The crystalline product which separates is washed with little ethylacetate and recrystallized three times from isopropyl alcohol to obtain(-)-N-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methyl-propionamidecamphosulfonate as a crystalline white solid melting at 154°-156° C.,(alpha)_(D) =+12.25° (c=5% , ethanol).

A solution of this salt is made alkaline with potassium carbonate andextracted with methylene chloride to give the corresponding free base inthe form of a colourless oil.

Operating in a similar way, the following compounds were prepared:

N-isopropyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropionamide

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 325(M+1)⁺ ;238

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 1.38 (6H, d); 1.58 (6H, s); 2.96(2H, m); 4.12 (3H, s); 4.21-4.38 (4H); 7.14-7.28 (4H).

N-butyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methyl-propionamide

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 339(M+1)³⁰ ; 238.

¹ H-NMR (300 MHz, CDCl₃): (ppm): 1.15 (3H, t); 1.58 (6H, s); 1.48-1.75(4H); 2.96 (2H, m); 3.45 (2H); q); 4.11 (3H, s); 4.20-4.63 (3H;)7.13-7.28 (4H).

2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methyl-propionamide

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 283(M+1)⁺ ; 238.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 1.35 (6H, s); 2.78 (2H, m); 3.85(3H, s); 3.98 (1H, dd); 4.05 (1H, m); 4.10 (1H, dd); 6.88-7.02 (4H, m).

N-methyl-3-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino-3-methyl-butyramide

Mass spectrum (chemical ionization, positive ions, NH₄ OH): m/e 311(M+1)⁺ ; 143.

¹ H-NMR (300 MHz), CDCl₃ : delta (ppm): 1.14 and 1.15 (6H, 2s); 2.26(2H, s); 2.73 (3H, d), 2.75 (2H, m), 3.75 (3H, s); 370-4.10 (3H);6.86-7.03 (4H).

N-methyl-2-(2-hydroxy-3-(1-naphthoxy)-propylamino)-2-methyl-propionamide

Mass spectrum (chemical ionization, positive ions, NH₄ OH) m/e 317(M+1)⁺ ;258.

¹ H-NMR (300 Mhz, CDCl₃): delta (ppm); 1.32 and 1.33 (6H, 2s); 2.65 (3H,d); 2.78 (1H, dd), 2.86 (1H, dd); 4.15-4.24 (3H); 6.80 (1H) d); 7.36(1H, t); 7.42-7.52 (3H); 7.80 (1H, bd); 8.20 (1H, bd).

N-methyl-2-(2-hydroxy-3-(4-carbazolyloxy)-propylamino)-2-methyl-propionamide

Mass spectrum (chemical ionization, positive ions, NH₄ HO) m/e 356(M+1)⁺ ; 297.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 1.35 (6H, s); 2.68 and 2.70 (3H,2s), 2.78-2.94 (2H); 4.20-4.30 (3H); 6.67 (1H, d); 7.08 (1H, d);7.18-7.44 (4H); 8.21 (1H, d)

The above mentioned compounds have been obtained in the form ofchromatographically pure oils (T.L.C.; eluent, methylenechloride:methanol:NH₄ OH=94.5:5:0.5)

EXAMPLE 6 Preparation of(-)-N-methyl-2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropionamide

A mixture of(-)-N-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methyl-propionanide(18.0 g; 0.061 moles), prepared as disclosed in example 4,triphenylmethyl chloride (17.5 g; 0.061 moles) and triethylamine (12 ml;0.085 moles) in toluene (180 ml) is refluxed under stirring for 10hours. After cooling to room temperature, the reaction mixture is washedwith water (100 ml), with a potassium bicarbonate aqueous solution (80ml) and finally with water (80 ml) again.

The organic phase is dried over sodium sulfate and filtered. The solidcrude product obtained after evaporation of the solvent, is purified bychromatography on silica gel column (230-400 mesh) eluting withmethylene chloride.(-)-N-methyl-2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropionamideis obtained as a chromatographycally pure oil (thin layerchromatography--eluent, ethyl acetate:gasoline=8:2). (alpha)_(D) =-40.2°(c=5%, ethanol).

¹ H-NMR (300 MHz, CDCl₃): delta (ppm); 1.14 (3H, s); 1.22 (3H, s); 2.33(1H, dd); 2.48 (3H, d); 2.68 (1H, dd); 3.55 (1H, dd); 3.76 (3H, s);4.00-4.10 (2H; 6.62 (1H, bd); 6.80-6.95 (3H, m); 7.20-7.35 (9H, m); 7.50(6H, bd).

Operating in a similar way, the following compounds were prepared:

N-isopropyl-2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropionamide

Chromatographically pure oil (thin layer chromatography--eluent,methylene chloride:methanol:NH₄ OH=98:4:0.2

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide);m/e 568 (M+2)³⁰ ; 325; 243.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 0.89 (3H, d); 0.92 (3H, d); 1.10(3H, s); 1.21 (3H, s); 2.42 (1H, dd); 2.57 (1H, dd); 3.64 (1H, dd); 3.75(3H, s); 3.87 (1H, m); 3.99 (1H, dd); 4.03 (1H, m); 6.63 (1H, bd);6.80-6.94 (3H); 7.20-7.32 (9H, m); 7.52 (6H, bd).

N-butyl-2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenyl-methylamino)-2-methylpropionamide

chromatographically pure oil (thin layer chromatography--eluent,methylene chloride:methanol:NH₄ OH=160:15/1)

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 581 (M+1)⁺ ; 339; 243.

¹ -HMR (300 MHz, CDCl₃): delta (ppm): 0.78 (3H, t); 1.12 (3H, s); 1.22(3H, s); 1.08-1.25 (4H); 2.37 (1H, dd); 2.58 (1H, dd); 2.85 (1H, m);3.05 (1H, m); 3.59 (1H, dd); 3.76 (3H, s); 4.01 (1H, dd); 4.01 (1H, m);6.63 (1H, bd); 6.80-6.95 (3H); 7.20-7.35 (9H); 7.50 (6H, bd).

2-((2-hydroxy-3-(2-methoxyphenoxy)propyltriphenylmethylamino)-2-methylpropionamide

Chromatographicaaly pure oil (thin layer chromatography--eluent,methylene chloride:methanol:NH₄ OH=160:15:1)

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 525 (M+1)⁺ ; 480; 243; 115.

¹ H-NMR (300 Mhz, CDCl₃): delta (ppm); 1.16 (3H, s); 1.25 (3H, s); 2.41(1H, dd); 2.60 (1H, dd); 3.61 (1H, dd); 4.01 (1H, dd); 4.04 (1H, m);6.58 (1H, bd); 6.80-6.94 (3H), m); 7.22-7.35 (9H, m); 7.50 (6H, bd).

EXAMPLE 7 Preparation of(-)-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)propyl)-triphenylmethylamino)-2-methoxypropyl)-methylamine

A solution of(-)-N-methyl-2-((2-hydroxy-3-(2-methoxyphenoxy)-proyl)-triphenylmethylamino)-2-methylpropionamide(25.1 g; 0.047 moles), prepared as described in example 6, intetrahydrofuran (200 ml) is added, dropwise under stirring and in ainert atmosphere, to a suspension of lithium aluminium hydride (3.55 g;0.093 moles) in anhydrous tetrahydrofuran (50 ml).

On completion of the addition, the reaction mixture is heated to refluxfor two hours.

After cooling on a ice bath, the lithium aluminum hydride excess isdecomposed by adding in succession dropwise a solution oftetrahydrofuran/water 9:1 (5 ml), and then water (4 ml), 15% sodiumhydroxide (4 ml), and again water (10 ml).

The precipitate is filtered and washed with ethyl ether; the organicphase is dried over sodium sulfate and filtered.(-)-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-methylamineis obtained by solvent evaporation.

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 526 (M+2)⁺ ; 243.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 0.92 (3H, s); 1.00 (3H, s); 2.30(3H, s); 2.34 (2H, s); 2.35-2.46 (2H, m); 3.68 (1H, dd); 3.80 (3H, s);4.01 (1H, dd); 4.05 (1H, m); 6.68 (1H, bd); 6.80-6.90 (3H, m); 7.20-7.34(9H, m); 7.52 (6H, bd).

Working in a similar way the following compounds were prepared:

N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyltriphenylmethylamino)-2-methylpropyl)-isopropylamine

chromatographycally pure oil (thin layer chromatography--eluent, CH₂ Cl₂:methanol:NH₄ OH=98:4:0.2)

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 554 (M+2)⁺ ; 243.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm); 0.88-0.95 (12H); 2.32 (2H, s);2.45 (2H, bd); 2.60 (1H; m); 3.62 (1H, ddd); 3.79 (3H, s); 3.94 (1H,dd); 3.98 (1H, m); 6.64 (1H, d); 6.83 (3H, m), 7.25 (9H, m); 7.52 (6H,bd).

N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyltriphenylmethylamino)-2-methylpropyl)-butylamine

chromatographycally pure oil (thin layer chromatography--eluent, CH₂ Cl₂:methanol:NH₄ OH=98:4:0.2

Mass spectrum (chemical ionization, positive ion, ammonium hydroxide):m/e 568 (M+2)⁺ ; 243

¹ H-NMR (300 MHz, CDCl₃); delta (ppm): 0.83 (3H, t); 0.92 (3H, s); 0.98(3H, s); 1.20 (2H, m); 1.33 (2H, m); 2.37 (2H, s); 2.40-2.52 (4H); 3.65(1H, dd); 3.80 (3H, s); 3.96 (1H, dd); 3.99 (1H, m); 6.65 (1H, bd); 6.74(3H, m); 7.26 (9H, m); 7.52 (6H, bd).

2-((2-hydroxy-3-(2-methoxyphenoxy)-propyltriphenylmethylamino)-2-methylpropyl)-methylpropylamine

chromatographycally pure oil (thin layer chromatography--eluent, CH₂ Cl₂:methanol:NH₄ OH=160:15:1)

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 512 (M+2)⁺ ; 480; 243.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm); 0.85 (3H, s); 0.89 (3H, s); 2.38(2H, s); 2.42 (2H, d); 3.70 (1H, dd); 3.80 (3H, s); 4.00 (2H, m), 6.65(1H, dd); 6.80-6.90 (3H, m); 7.20-7.30 (9H, m); 7.50-7.55 (6H, m).

EXAMPLE 8 Preparation of (-)N-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)propylamino)-2-methylpropylamineoxalate

A solution of (-)N-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyionamide(50 g; 0.017 moles), prepared as described in example 4b, and boranemethyl sulfite (78.2 ml; 0.82 moles) in tetrahydrofuran (500 ml) ismaintained under reflux for 3 hours under nitrogen atmosphere.

The reaction mixture is cooled to 5° C. and a solution of concentrateHCl (35 ml) in methanol (200 ml) is slowly added; the mixture is thenrefluxed for 1 hour. The solvent is evaporated and the crude iscollected with water (100 ml). The mixture is made alkaline to pH 8 withdilute ammonia. After addition of potassium bicarbonate till saturation,the mixture is extracted with methylene chloride. The organic phase isdried over sodium sulphate, filtered and evaporated to dryness. Theresidue is dissolved in hot ethyl acetate (300 ml). The mixture iscooled and a solution of oxalic acid in ethyl acetate is added till acidpH.

After half an hour at room temperature, the crystalline solid isseparated by filtration, washed with ethyl acetate and then with ethylether. After drying, (-)N-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-methylpropylamino)-2-propylamineoxalate is obtained in the form of a whithe solid melting at 150°-152°C.

The base shows an (alpha)_(D) =-10.8 (water, c=0.5%)

Working in a similar way the following compounds were prepared:

N-methyl-3-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-3-methylbutylamine

White solid, m.p. 93° C.

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide;m/e 297 (M+1)⁺ ;

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 1.11 (6H, s); 1.62 (2H, bt); 2.42(3H, s); 2.70 (2H, bt); 2.73 (1H, dd), 2.86 (1H, dd); 3.83 (3H, s); 4.01(1H, m); 4.2 (2H, bs), 6.84-6.95 (4H).

N-methyl-2-(2-hydroxy-3-(1naphthoxy)-propylamino)-2-methylpropylamine

Chromatographically pure oil (T.L.C.; eluent, methylenechloride:methanol:ammonium hydroxide=86:10:0.6)

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 303 (M+1)⁺ ; 258

¹ H-NMR (300 MHz, CDCl₃): delta(ppm); 1.07 and 1.08 (6H, 2s); 2.41 (3H,s); 2.47 (2H, d); 2.75 (1H, dd); 2.92 (1H, dd); 4.08-4.21 (3H); 6.82(1H, d); 7.32-7.50 (4H); 7.79 (1H, m). 8.25 (1H, m).

N-methyl-2-(2-hydroxy-3-(4-carbazolyloxy)-propylamino)-2-methylpropylamine

Chromatographically pure oil (T.L.C.; eluent, methylenechloride:methanol:NH₄ OH=86:10:0.6)

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 342 (M+1)⁺ ;29

¹ H-NMR (300 Mhz, CDCl₃) delta (ppm): 1.09 and 1.11 (6H, 2s); 2.42 (3H,s); 2.50 (2H, d); 2.85 (1H, dd); 3.00 (1H, dd); 4.12-4.30 (3H); 6.66(1H, d); 7.02 (1H, d); 7.18-7.40 (3H); 8.29 (1H, d)

EXAMPLE 9 Preparation of ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

A mixture of(-)-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-methylamine(23.4 g; 0.045 moles) prepared as disclosed in example 7,2-bromoethyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate(20.2 g; 0.045 moles) and triethylamine (9.2 ml; 0.066 moles) in toluene(230 ml) is stirred at room temperature for three hours.

The reaction mixture is washed with water (200 ml), with a saturatepotassium bicarbonate solution (150 ml) and again with water (100 ml).

After drying over sodium sulfate the organic phase is filtered and thesolvent evaporated.

The reaction crude product is purified by chromatography on silica gelcolumn (230-400 mesh), eluent--petroleum ether; ethylacetate:ethanol:propylamine=100:100:0.5:1. Ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylateis obtained.

The chromatographic analysis (thin layer chromatography--eluent, CH₂ Cl₂:methanol:NH₄ OH=98.2:2:0.2) shows two spots corresponding to the twoenantiomers of the two diastereomeric pairs.

Mass spectrum (chemical ionization, negative ions, isobutane): m/e 654(M-CPh₃)⁻ ; 623;415;123.

¹ H-NMR (300 MHz, CDCl₃) delta (ppm): 0.90-1.40 (6H, 4s); 1.16-1.26 (6H,m); 2.20 (3H, 2s) 2.28 (3H, s); 2.24-2.40 (2H, m); 2.50-2.70 (2H, m);3.75 (3H, s); 3.84-4.15 (7H); 5.01 and 5.50 (1H, 2s); 6.30 (1H, bd);6.70-6.90 (3H, m); 7.20-7.32 (9H, m); 7.47-7.52 (7H); 7.59 (1H, bd);7.96 (1H, m); 8.11 (1H, bs).

Working in a similar way, the following compounds were prepared:

ethyl1,4-dihydro-6-methyl-2-(N-isopropyl-N-(2-((2-hydroxy-3(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

(thin layer chromatography--eluent, CH₂ Cl₂ :methanol:NH₄ OH=98:2:0.2,two spots corresponding to the two racemic diastereoisomers)

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 0.90-1.30 (18H); 2.15-2.40 (5H);2.60-2.80 (2H, m); 3.50 (1H, dd); 3.70 (2H, bd); 3.74 (3H, s); 5.01 and5.05 (1H, 2s); 6.50 (1H, bd); 6.80 (3H, m); 7.28 (9H, m), 7.44-7.52(7H); 7.60 (1H, m); 7.95 (1H, bd); 8.12 (1H, bd).

ethyl1,4-dihydro-6-methyl-2-(N-butyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

(thin layer chromatography--eluent, CH₂ Cl₂ :methanol:NH₄ OH=98:2:0.2)

Mass spectrum (chemical ionization, negative ions, isobutane): m/e 936(M+1)⁻ ; 694; 664; 457; 444.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 0.82 and 0.84 (3H, 2t); 0.92-1.04(6H, 4s); 1.16 (2H, m); 1.22 (6H, m); 1.34 (2H, m); 2.18 and 2.21 (3H,2s; 2.30-2.46 (4H); 2.60 (2H, m); 3.59 (2H, m); 3.75 (3H, s), 3.80-4.12(7H); 5.01 and 5.05 (1H, 2s); 6.52 (1H, bd); 6.80 (3H, m), 7.25 (9H, m);7.50 (7H); 7.57 (1H, bd); 7.95 (1H, bd); 8.10 (1H, bs).

ethyl,1,4-dihydro-6-methyl-2-(N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

(thin layer chromatography--eluent, CH₂ Cl₂ :methanol:NH₄ OH=98:2:0.2)

Mass spectrum (chemical ionization, negative ions, isobutane): m/e 882(M)⁻ ; 640; 402; 243;123.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 0.93-1.10 (6H); 1.16-1.25 (6H,2t); 2.15-2.54 (7H); 3.62-3.83 (3H, m); 3.80 (3H, s); 3.98-4.10 (6H, m);5.08 (1H, bd); 6.64 (1H, bd); 6.76-6.90 (3H, m); 7.20-7.48 (10H); 7.52(6H, bd); 7.59 (1H, bd); 7.98 (1H, bd); 8.09 (1H, bs); 8.44 (1H, bs).

EXAMPLE 10 Preparation of ethyl(-)-1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Concentrate hydrochloric acid (7 ml) is added to a solution of ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate(3.4 g; 3.9 mmoles, prepared as described in example 9, intetrahydrofuran (40 ml). After one hour at room temperature the solventis evaporated in vacuum at 40° C.

The crude product is dissolved in methylene chloride (60 ml), washedwith an aqueous potassium bicarbonate solution (40 ml) and with water(40 ml).

After drying over soodium sulfate, the organic phase is filtered and thesolvent is evaporated.

The crude product is chromatoographed on a silica gel column (230-400mesh) eluting with petroleum ether:ethylacetate:ethanol:triethylamine=10:10:0.2:0.5.

The two levorotatory enantiomers of the two racemic pairs ofdistereomeric ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenyl)-propylamino)-2-methoxylpropyl)aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarbooxylateare thus separated and then converted in their dihydrochloride salts bydissolution in ethyl ether and treatment with an anhydrous saturatesolution of HCl in ethyl ether.

Diastereoisomer A (greater Rf) (dihydrochloride), crystalline yellowsolid; m.p.=138°-141° C.; (alpha)_(D) =15.3° (c=5%, dimethylsulfoxyde).

Diatereoisomer B (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=110°-115° C.; (alpha)_(D) =+5.7 (c=5%, dimethylsulfoxyde).

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 655(M+1)⁺ ; 625; 531; 238.

Diatereoisomer A:

¹ H-NMR (free base) (300 MHz, CDCL₃): delta (ppm): 1.12 (3H, s); 1.14(3H, s); 1.20 (3H, t); 1.22 (3H, t); 2.38 and 2.39 (6H, 2s); 2.54 (2H,d); 2.70-2.85 (2H, m); 3.84 (3H, s); 3.91 (2H, s); 3.96-4.14 (7H); 5.06(1H, s); 6.85-6.98 (4H); 7.35 (1H, t); 7.62 (1H, bd); 7.97 (1H, bd);8.12 (1H, t).

Diatereoisomer B:

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm): 1.12 (3H, s); 1.14(3H, s); 1.20 (3H, t); 1.22 (3H, t) 2.38 and 2.39 (6H, 2s); 2.54 (2H,d); 2.70-2.85 (2H, m); 3.84 (3H,s); 3.91 (2H, s); 3.96-4.14 (7H); 5.06(1H, s); 6.85-6.98 (4H); 7.34 (1H, t); 7.62 (1H, bd); 7.97 (1H, bd);8.12 (1H, t).

Working in a similar way, the following compounds were prepared:

ethyl1,4-dihydro-6-methyl-2-(N-isopropyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer C (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=117°-120° C.

Diastereoisomer D (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=119°-122° C.

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 683(M+1)⁺ ; 653; 560; 444; 432; 238; 201; 125.

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm)

Diastereoisomer C: 113 and 1.15 (6H, 2d); 1.11 and 1.12 (6H, 2s); 1.21and 1.22 (6H, 2t); 2.40 (3H, s); 2.50 (2H, bs); 2.73-2.90 (5H); 3.84(3H, s); 3.95-4.15 (7H); 5.09 (1H, s) 6.90 (4H, m); 7.33 (1H, t); 7.61(1H, bd); 7.96 (1H, bd); 8.10 (1H, bs).

Diastereoisomer D: 1.13 and 1.15 (6H, 2d); 1.11 and 1.13 (6H, 2s); 1.21and 1.22 (6H, 2t); 2.39 (3H, s); 2.51 (2H, dd); 2.73-2.90 (5H); 3.84(3H, s); 3.95-4.15 (7H); 5.09 (1H, s) 6.90 (4H, m); 7.33 (1H, t); 7.61(1H, bd); 7.96 (1H, bd); 8.10 (1H, bs).

ethyl1,4-dihydro-6-methyl-2-(N-butyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer E (greater Rf) (dihydrochloride), crystalline yellowsolid; m.p.=108°-110° C.

Diastereoisomer F (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=113°-120° C.

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 697(M+1)⁺ ; 458;446;257;201;125.

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm)

Diastereoisomer E: 0.90 (3H, t); 1.10 and 1.11 (6H, 2s; 1.21 and 1.22(6H, 2t); 1.30 (2H, m); 1.43 (2H, m); 2.39 (3H, s); 2.50-2.75 (8H); 3.84(3H, s); 3.90-4.15 (7H); 5.08 (1H, s); 6.90 (4H, m); 7.33 (1H, t); 7.61(1H, bd); 7.96 (1H, bd); 8.11 (1H, bs).

Diastereoisomer F: 0.90 (3H, t); 1.10 and 1.12 (6H, 2s); 1.21 and 1.22(6H, 2t); 1.30 (2H, m); 1.43 (2H, m); 2.38 (3H, s); 2.50-2.75 (8H); 3.84(3H, s); 3.90-4.15 (7H); 5.08 (1H, s); 6.90 (4H, m); 7.33 (1H, t); 7.61(1H, bd); 7.96 (1H, bd); 8.11 (1H, bs).

EXAMPLE 11 Preparation of ethyl1,4-dihydro-6-methyl-2-(N-ethyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

A mixture of ethyl1,4-dihydro-6-methyl-2-(N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate(20.6 g; 23.4 mmoles), prepared as disclosed in example 9,diethylsulfate (3.3 ml; 25.3 mmoles), triethylamine (5 ml; 34.6 mmoles)and tetrabutylammonium hydrogen sulfate (2.4 g; 7.0 mmoles) in toluene(200 ml) is heated to reflux for 5 hours.

After evaporation of the solvent, the crude product is extracted withmethylene chloride (200 ml) and water (100 ml).

The organic phase is separated, dried over sodium sulfate and filtered.By solvent evaporation a crude product is obtained, which is purified bychromatography on silica gel column (230-400 mesh), eluting withpetroleum ether:ethyl acetate:propylamine=120:89:0.3.

Chromatographically pure ethyl1,4-dihydro-6-methyl-2-(N-ethyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylateis thus obtained.

¹ H-NMR (300 MHz, CDCl₃): delta (ppm) 0.9-1.5 (9H); 1.18-1.25 (6H, m);2.18 and 2.22 (3H, 2s); 2.25-2.74 (6H, m); 3.75 (3H, s); 3.78-4.10 (9H,m); 5.01 and 5.06 (1H, 2s); 6.51 (1H, bd); 6.65-6.88 (3H, m); 7.18-7.31(9H, m); 7.45-7.53 (7H, m); 7.58 (1H, bd); 7.95 (1H, bd); 8.10 (1H, bs);9.02 and 9.12 (1H, bs).

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 910(M)⁺ ; 699; 417.

Working in a similar way but using allyl iodide and benzyl bromide,respectively, as alkylating agents the following compounds wereprepared.

Ethyl1,4-dihydro-6-methyl-2-(N-2-propenyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

¹ H-NMR (300 MHz, CDCl₃): delta (ppm): 0.90-1.05 (6H, 4s); 1.16-1.20(6H, m); 2.18 and 2.24 (3H, 2s); 2.39 (2H, dd); 2.50-2.75 (2H, m);3.00-3.20 (2H, m); 3.50-4.15 (9H); 3.74 (3H, s); 4.90-5.80 (3H, m);5.70-5.80 (1H, m); 6.50 (1H, dd); 6.70-6.88 (3H, m); 7.20-7.32 (9H, m);7.45-7.60 (8H, m); 7.95 (1H, bd); 8.10 (1H, bs).

ethyl1,4-dihydro-6-methyl-2-(N-benzyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

¹ H-NMR (300 MHz, CDCl₃): delta (ppm) 0.85-0.95 (6H, m); 2.20 and 2.28(3H, 2s); 2.30-2.78 (4H); 3.72 and 3.74 (3H, 2s); 3.50-4.10 (11H); 4.98(1H, bs); 6.46 (1H, m); 6.65-6.86 (3H, m); 7.10-7.30 (16H, m); 7.45-7.54(6H, m); 7.92 (1H, bd); 8.10 (1H, bd).

EXAMPLE 12 Preparation of ethyl1,4-dihydro-6-methyl-2-(N-ethyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Concentrate hydrochloric acid (7.1 ml) is added to a solution of ethyl1,4-dihydro-6-methyl-2-(N-ethyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate(3.5 g; 3.9 mmoles), prepared as disclosed in example 11, intetrahydrofuran (40 ml). After one hour at room temperature the solventis evaporated in vacuum at 40° C. The crude solid is dissolved inmethylene chloride (60 ml), washed with a potassium bicarbonate saturateaqueous solution (40 ml) and the organic phase is dried over sodiumsulfate and filtered.

After evaporation of the solvent, the crude product is purified bychromatography on silica gel column (230-400 mesh) eluting withpetroleum ether:ethyl acetate;triethyl amine:ethanol=10:10:0.5:0.2.

The two ethyl1,4-dihydro-6-methyl-2-(N-ethyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate diastereoisomers arethus separated and then converted in their dihydrochloride salts bytreatment with a solution of hydrochloric acid in ethyl ether.

Diastereoisomer G: (greater Rf) (dihydrochloride), amorphous yellow,solid; m.p.=116°-118° C.

Diastereoisomer H: (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=117°-120° C.

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 670(M+2)⁺ ; 238.

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm)

Diastereoisomer G: 1.10 and 1.11 (6H, 2s); 1.20 (3H, t); 1.22 (3H, t);2.40 (3H, s); 2.55 (2H, bs); 2.62 (2H, q); 2.75-2.88 (2H, m); 3.84 (3H,s); 3.90-4.15 (7H); 5.08 (1H, s); 6.86-6.98 (4H, m); 7.33 (1H, t); 7.51(1H, bd); 7.96 (1H, bd); 8.10 (1H, bs).

Diastereoisomer H: 1.10 and 1.12 (6H, 2s); 1.20 (3H, t); 1.22 (3H, t);2.40 (3H, s); 2.55 (2H, bs); 2.62 (2H, q); 2.75-2.88 (2H, m); 3.84 (3H,s); 3.90-4.15 (7H); 5.078 (1H, s); 6.86-6.98 (4H, m); 7.33 (1H, t); 7.51(1H, bd); 7.96 (1H, bd); 8.10 (1H, bs).

Working in a similar way, the following compounds were prepared:

ethyl1,4-dihydro-6-methyl-2-(N-2-propenyl-N-(2-2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer I: (greater Rf)

Diastereoisomer J: (lower Rf)

Both the diastereoisomers I and J (dihydrochloride) melt at 90°-95° C.

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 681 (M+1)⁺ ; 238.

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm)

Diastereoisomer I: 1.10 and 1.11 (6H, 2s); 1.20 and 1.22 (6H, 2t); 2.40(3H, s); 2.57 (2H, bs); 2.76 (2H, m); 3.18 (2H, d); 3.85 (3H, s);3.90-4.15 (9H); 5.08 (1H, s); 5.12 (1H, m); 5.18 (1H, bs); 5.85 (1H, m);6.84-6.98 (4H); 7.34 (1H, t); 7.11 (1H, bd); 7.97 (1H, dd); 8.11 (1H,bs).

Diastereoisomer J: 1.10 and 1.12 (6H, 2s); 1.20 and 1.22 (6H, 2t); 2.40(3H, s); 2.57 (2H, bs); 2.76 (2H, m); 3.18 (2H, 2d); 3.85 (3H, s);3.90-4.15 (9H); 5.08 (1H, s); 5.12 (1H, m); 5.18 (1H, bs); 5.85 (1H, m);6.84-6.98 (4H); 7.34 (1H, t); 7.11 (1H, bd); 7.97 (1H, dd); 8.11 (1H,bs).

Ethyl1,4-dihydro-6-methyl-2-(N-benzyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer K: (greater Rf)

Diastereoisomer L: (lower Rf)

Both the diastereoisomers K and L (dihydrochloride) melt at 90°-95° C.

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 731 (M+1)⁺ ; 238

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm):

Diastereoisomer K: 1.04 and 1.05 (6H, 2s); 1.18 and 1.20 (6H, 2t); 2.38(3H, s); 2.71 (2H, d); 2.79 (2H, d); 3.72 (2H, dd); 3.83 (3H, s);3.90-4.24 (9H); 5.01 (1H, s); 6.88 (3H, m); 6.95 (1H, m); 7.15-7.34(6H); 7.52 (1H, bd); 7.95 (1H, bd); 8.10 (1H, bs).

Diastereoisomer L: 1.04 and 1.05 (6H, 2s); 1.18 and 1.20 (6H, 2t); 2.37(3H, s); 2.71 (2H, d); 2.79 (2H, d); 3.72 (2H, dd); 3.83 (3H, s);3.90-4.24 (9H); 5.01 (1H, s); 6.88 (3H, m); 6.95 (1H, m); 7.15-7.34(6H); 7.52 (1H, bd); 7.95 (1H, bd); 8.10 (1H, bs).

EXAMPLE 13 Preparation of methyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

A mixture of(-)-N-methyl-2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropylamine(6.4 g, 22.6 mmoles), methyl2-chloromethyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate(9.6 g, 22.6 mmoles) and triethylamine (6.1 ml, 42.3 mmoles) in tolueneis maintained at room temperature for 3 hours.

The reaction mixture is washed with water (100 ml), with a saturesolution of potassium bicarbonate (75 ml) and with water (50 ml) again.

The organic phase is dried over sodium sulfate and filtered; the solventis evaporated. The crude product is purified and the twodiastereoisomers are separated by chromatography on silica gel (230-400mesh) column; eluent, ethyl acetate:toluene:ammonium hydroxide=90:10:1.The two diastereoisomer of methyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylateare thus obtained and then treated with a solution of hydrogen chloridegas in ethyl ether to give the corresponding dihydrochloride salts.

Diastereoisomer M: (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=138°-140° C.; (alpha)_(D) =-7.5 (c=0.5%, ethanol).

Diastereoisomer N: (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=134°-137° C.; (alpha)_(D) =-4.0 (c=0.5% ethanol).

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 627 (M+1)⁺ ; 376; 335; 283; 238.

Diastereoisomer M:

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.12 (6H, s); 2.40(6H, s); 2.52 (2H, s); 2.76 (2H, m); 3.61 and 3.64 (6H, 2s); 3.83 (3H,s); 3.91 (2H, d); 3.96-4.10 (3H); 5.09 (1H, s); 6.84-6.98 (4H); 7.35(1H, t); 7.61 (1H, bd); 7.96 (1H, bd), 8.09 (1H, bs).

Diastereoisomer N:

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.11 and 1.13 (6H, 2s); 2.38 (3H, s); 2.39 (3H, s); 2.53 (2H, dd); 2.78 (2H, m); 3.63 and3.65 (6H, 2s); 3.84 (3H, s); 3.91 (2H, d); 3.95-4.10 (3H); 5.09 (1H, s);6.84-6.98 (4H); 7.35 (1H, t); 7.61 (1H, bd); 7.96 (1H, dd); 8.09 (1H,bs).

Working in a similar way, the following compounds were prepared:

isopropyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropylaminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer O: (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=150°-152° C.

Diastereoisomer P: (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=125°-128° C.

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 683 (M+1)⁺ ; ; 238; 238.

Diastereoisomer O

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.08 (6H, 2d); 1.12(6H, s); 1.25 (6H, d); 2.37 and 2.39 (6H, 2s); 2.52 (2H, s); 2.80 (2H,m); 3.84 (3H, s); 3.91 (2H, d); 3.98-4.10 (3H); 4.92 (2H, 2m); 5.05 (1H,s) 6.85-7.00 (4H); 7.35 (1H, t), 7.61 (1H, bd); 7.96 (1H, dd); 8.11 (1H,bs).

Diastereoisomer P

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm): 1.06-1.14 (12H); 1.24and 1.26 (6H, 2s), 2.37 and 2.39 (6H, 2s); 2.51 (2H, s); 2.76 (2H, m);3.84 (3H, s); 3.09 (2H, s); 3.98-4.10 (3H); 4.92 (2H, 2m), 5.04 (1H, s);6.85-7.00 (4H); 7.33 (1H, t); 7.61 (1H, bd); 7.97 (1H, dd); 8.11 (1H,bs).

2-methoxyethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer Q: (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=125°-127° C.

Diastereoisomer R: (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=127°-128° C.

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 715 (M+1)⁺ ; ; 283; 238.

Diastereoisomer Q

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm): 1.12 (6H, s); 2.39(6H, s) 2.51 (2H, s), 2.77 (2H, m); 3.33 and 3.34 (6H, 2s); 3.54 (4H,m); 3.84 (3H, s); 3.90 (2H, d); 3.95-4.22 (7H); 5.11 (1H, s); 6.84-6.98(4H); 7.34 (1H, t); 7.66 (1H, bd); 7.96 (1H, dd); 8.11 (1H, bs).

Diastereoisomer R

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm): 1.11 and 1.13 (6H,2s), 2.39 (6H, s), 2.51 (2H, d); 2.75 (2H, m); 3.33 and 3.34 (6H, 2s);3.54 (4H, m); 3.83 (3H, s); 3.90 (2H, s); 3.97-4.22 (7H); 5.11 (1H, s);7.34 (1H, t); 7.67 (1H, bd); 7.97 (1H, dd); 8.11 (1H, bs).

methyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-5-carbethoxy-3-pyridinecarboxylate

Diastereoisomer S: (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=120°-122° C.

Diastereoisomer T: (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=100°-102° C.

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 641 (M+1)⁺ ; ; 238.

Diastereoisomer S

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.11 (6H, 1); 1.23(3H, t), 2.36 and 2.37 (6H, 2s); 2.51 (2H, s); 2.75 (2H, m); 3.61 (3H,s); 3.74 (3H, s); 3.90 (2H, d); 3.95-4.15 (5H); 5.08 (1H, s); 6.85-7.00(4H), 7.34 (1H, t); 7.61 (1H, bd); 7.96 (1H, dd); 8.10 (1H, bs).

Diastereoisomer T

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.11 and 1.13 (6H,2s); 1.22 (3H, t); 2.36 and 2.38 (6H, 2s); 2.52 (2H dd); 2.75 (2H, m);3.61 (3H, s); 3.84 (3H, s); 3.90 (2H, s); 3.96-4.15 (5H); 5.08 (1H, s);6.85-7.00 (4H); 7.34 (1H, t); 7.61 (1H, bd), 7.96 (1H, dd); 8.10 (1H,bs)

ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-5-carboxymethyl-3-pyridinecarboxylate

Diastereoisomer U: (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=139°-141° C.

Diastereoisomer V: (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=129°-132° C.

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 641 (M+1)⁺ ; ; 611; 238.

Diastereoisomer U

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.12 (6H, s); 1.22(3H, t), 2.38 (6H, s); 2.51 (2H, s); 2.78 (2H, m); 3.64 (3H, s); 3.84(3H, s); 3.91 (2H, d); 3.95-4.15 (5H); 5.08 (1H, s); 6.84-6.98 (4H);7.35 (1H, t); 7.61 (1H, d); 7.98 (1H, dd); 8.11 (1H, bs)

Diastereoisomer V

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm): 1.12 and 1.13 (6H,2s); 1.22 (3H, t); 2.37 and 2.38 (6H, 2s); 2.53 (2H, ab); 2.70 (2H, m);3.64 (3H, s); 3.83 (3H, s); 3.91 (2H, d); 3.96-4.12 (5H); 5.08 (1H, s);6.84-7.00 (4H); 7.34 (1H, t); 7.61 (1H, bd); 7.98 (1H, dd); 8.11 (1H,bs).

ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(2-trifluoromethyl)-3,5-pyridinedicarboxylate

Diastereoisomer W: (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=117°-120° C.;

Diastereoisomer X: (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=113°-115° C.;

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 678 (M+1)⁺ ;; 283; 238.

Diastereoisomer W

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.11 and 1.12 (6H,2s); 1.16 and 1.17 (6H, 2t); 2.33 and 2.35 (6H, 2s); 2.50 (2H, s); 2.77(2H, m); 3.84 (3H, s); 3.85 (2H, dd); 3.93-4.20 (7H); 5.60 (1H, bs);6.86-7.00 (4H); 7.20 (1H, m); 7.37 (1H, bt); 7.46 (1H, bd); 7.51 (1H,bd).

Diastereoisomer X:

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.11 and 1.12 (6H,2s); 1.16 and 1.17 (6H, 2t); 2.50 (2H, s); 2.77 (2H, m); 3.84 (6H, s)3.85 (2H, bs) 3.90-4.20 (7H); 5.60 (1H, bs); 6.85-7.00 (4H); 7.20 (1H,m) 7.36 (1H, bt); 7.46 (1H, dd); 7.51 (1H, bd).

ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(2-chlorophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer Y: (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=115°-118° C.;

Diastereoisomer Z: (lower Rf) (dihydrochloride), amorphous yellow solid;m.p.=108°-110° C.;

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 644 (M+1)⁺ ;; 238.

Diastereoisomer Y:

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.11 (6H, s), 1.19(6H, bt); 2.32 and 2.35 (6H, 2s); 2.50 (2H, s); 2.75 (2H, m); 3.83 (3H,s); 3.85 (2H, dd); 3.95-4.10 (7H); 5.40 (1H, s); 6.85-7.40 (8H).

Diastereoisomer Z:

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.12 (6H, bs)); 1.19(6H, t); 2.32 and 2.36 (6H, 2s); 2.51 (2H, s); 2.80 (2H, m); 3.83 (3H,s); 3.86 (2H, bs); 4.00-4.12 (7H); 5.40 (1H, s); 6.85-7.40 (8H).

ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer AA: (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=112°-114° C.;

Diastereoisomer AB: (lower Rf) (dihydrochloride), amorphous yellowsolid; m.p.=118°-121° C.;

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 678 (M+1)⁺ ;; 238.

Diastereoisomer AA:

¹ H-NMR (free base) (300 Mhz, CDCl₃) delta (ppm) 1.11 (6H, bs); 1.18(6H, 2t); 2.32 and 2.35 (6H, 2s); 2.50 (2H, s); 2.76 (2H, m); 3.84 (3H,s); 3.85 (2H, dd); 3.96-4.10 (7H); 5.47 (1H, s); 6.85-7.00 (4H); 7.03(1H, t); 7.22 (1H, dd); 7.29 (1H, dd)

Diastereoisomer AB:

¹ H-NMR (300 Mhz, CDCl₃): delta (ppm) 1.11 (6H, 2s); 1.18 (6H, 2t), 2.33and 2.35 (6H, 2s); 2.50 (2H, s); 2.76 (2H, m), 3.84 (3H, s); 3.85 (2H,bs), 3.98-4.10 (7H); 5.46 (1H, s); 6.85-7.00 (4H), 7.02 (1H, t); 7.22(1H, bd); 7.29 (1H, dd).

ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(1-naphthoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer AC: (greater Rf) (dihydrochloride), amorphous yellowsolid; m.p.=128°-131° C.;

Diastereoisomer AD: (lower Rf) (dihydrochloride), amorphous yellowsolid; m.p.=122°-125° C.;

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 675 (M+1)⁺ ;; 643; 258.

Diastereoisomer AC:

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.14 (6H, 2s); 1.19(6H, 2t); 2.35 and 2.40 (6H, 2s); 2.54 (2H, s); 2.90 (2H, 2m), 3.92 (2H,dd); 4.00-4.22 (7H); 5.07 (1H, s); 6.80 (1H, d); 7.30-8.20 (10 H).

Diastereoisomer AD

¹ H-NMR (free base) (30 MHz, CDCl₃): delta (ppm) 1.15 (6H, 2s); 1.20(6H, 2t); 2.36 and 2.40 (6H, 2s); 2.54 (2H, s); 2.90 (2H, 2m); 3.94 (2H,bd); 4.00-4.22 (7H); 5.08 (1H, s); 6.80 (1H, d), 7.30-8.20 (10H).

ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(3-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-3-methylbutyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Diastereoisomers mixture (dihydrochloride), amorphous yellow solid;

Mass spectrum (chemical ionization, positive ions, isobutane) m/e 699(M+1)⁺ ;; 543.

¹ H-NMR (free base) (300 Mhz, CDCl₃): delta (ppm) 1.12 and 1.20 (6H,2s); 1.14-1.25 (6H); 1.60 and 1.72 (2H, 2 m); 2.32 and 2.33 (2H, 2s);2.38 (3H, s); 2.65 (2H, m); 2.76 (1H, dd); 2.90 (1H, dd); 3.62-3.78(2H); 3.83 (3H, 2s); 3.98-4.15 (7H); 5.09 and 5.11 (1H, 2s); 6.85-6.98(4H); 7.35 (1H, bt); 7.60 (1H, bd); 7.98 (1H, dd); 8.10 (1H, m).

ethyl1,4-dihydro-6-methyl-2-(N-methyl-N-(2-(2-hydroxy-3-(1-carbazolyloxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Diastereoisomer AE: (greater RF) (dihydrochloride), amorphous yellowsolid; m.p.=151°-154° C.;

Diastereoisomer AF: (lower Rf) (dihydrochloride), amorphous yellowsolid; m.p.=149°-151° C.;

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide)m/e 714 (M+1)⁺ ;; 402; 378; 297; 184.

Diastereoisomer AE:

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.16 (6H, bs); 1.20(6H, 2t); 2.32 (3H, s); 2.39 (3H, s); 2.53 (2H, bs); 2.97 (2H, m); 3.91(2H, dd); 4.00-4.34 (7H); 5.06 (1H, s); 6.66 (1H, d); 7.06 (1H, d);7.15-7.44 (5H): 7.61 (1H, bs); 7.95 (1H, dd); 8.11 (1H, bs); 8.22 (1H,d).

Diastereoisomer AF:

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm) 1.16 (6H, bs); 1.21(6H, 2t), 2.34 (3H, s); 2.39 (3H, s); 2.54 (2H, bs); 2.98 (2H, m); 3.91(2H, bs); 4.00-4.34 (7H); 5.08 (1H, s); 6.66 (1H, d); 7.06 (1H, d);7.15-7.44 (5H); 7.61 (1H, bs); 7.95 (1H, dd); 8.11 (1H, bs); 8.22 (1H,d).

EXAMPLE 14 Preparation of Ethyl1,4-dihydro-6-methyl-2-(N-acetyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

A mixture of ethyl1,4-dihydro-6-methyl-2-(N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate(5 g; 5.6 mmoles), prepared according to example 9, acetic anhydride(0.53 ml; 5.6 mmoles), pyridine (0.45 ml; 5.6 mmoles) in toluene (50 ml)is kept at room temperature for two hours.

The reaction mixture is diluted with ethyl acetate (50 ml,) the organicphase is washed with water (30 ml), then with a potassium bicarbonatesolution (40 ml) and eventually with water (30 ml).

After anhydrification of the organic extract with sodium sulfate andevaporation of solvent, the crude product is purified by chromatographyon silica gel (230-400 mesh) column eluting with ethyl acetate:petroleumether:ethanol:propylamine=100:100:0.5:1.

Chromatography pure Ethyl1,4-dihydro-6-methyl-2-(N-acetyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinecarboxylateis thus obtained (thin layer chromatography; eluent, CH₂ Cl₂:methanol:NH₃ OH=98:4:0,2).

Mass spectrum (chemical ionization, positive ions, ammonium hydroxide):m/e 681 (M--CPh₃)⁺ ; 342; 243.

IR (CHCl₃): characteristic bands at 3300, 3200, 1700, 1650, 1600, 1530,1500 (cm⁻¹).

Working in a similar way but using benzoyl chloride, isobutyrylchloride, ethyl chlorocarbonate and methane sulfonyl chloride asacylating agents, the following compounds were prepared:

Ethyl1,4-dihydro-6-methyl-2-(N-benzoyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

IR (CHCl₃): characteristic bands at 3300, 3200, 1690, 1640, 1600, 1530,1500 (cm⁻¹).

Ethyl1,4-dihydro-6-methyl-2-(N-(1-oxo-2-methylpropyl)-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 953(M+1)⁺ ; 710; 458; 342; 243.

IR (CHCl₃): bands at 3300, 3220, 1690, 1640, 1600, 1530, 1500 (cm⁻¹).

Ethyl1,4-dihydro-6-methyl-2-(N-ethoxycarbonyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Mass spectrum (chemical ionization, negative ions, isobutane): m/e 955(M+1)⁻ ; 909; 666; 372; 342.

IR (CHCl₃); characteristic bands at 3300, 3200, 1690, 1640, 1600, 1530,1500 (cm⁻¹).

Ethyl1,4-dihydro-6-methyl-2-(N-methylsulfonyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)-triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Mass spectrum (chemical ionization, negative ions, isobutane): me/ 881(M--CH₃ SO₂)⁻ ; 718; 638; 401; 372; 243.

IR (CHCl₃): characteristic bands at 3320, 3200, 1690, 1650, 1630, 1600,1530, 1500, (cm⁻¹).

EXAMPLE 15 Preparation of Ethyl1,4-dihydro-6-methyl-2-(N-acetyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

Concentrate HCl (29 ml) is added to a solution of Ethyl1,4-dihydro-6-methyl-2-(N-acetyl-N-(2-((2-hydroxy-3-(2-methoxyphenoxy)-propyl)triphenylmethylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinecarboxylate(14.4 g; 15.6 mmoles), prepared as disclosed in example 14, intetrahydrofuran (150 ml).

After half an hour at room temperature, the solvent is evaporated.

The crude product is extracted with methylene chloride and an aqueoussolution of potassium bicarbonate; the organic phase is washed withwater and dried over sodium sulfate.

After evaporation of the solvent, the crude product is purified bychromatography on a silica gel column (230-400 mesh) eluting withmethylene chloride:methanol:NH₄ OH=100:5:0.5.

Ethyl1,4-dihydro-6-methyl-2-(N-acetyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylateis thus obtained in the form of a yellow oil chromatographycally pure(thin layer chromatography; eluent, CH₂ Cl₂ :methanol:NH₄ OH=100:5:0.5).Hydrochloride: amorphous solid; p.f.=98°-100° C.

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 683(M+1)⁺ ; 665; 648; 575; 508.

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm): 1.15-1.25 (12H);2.05-2.43 (6H, 5s); 2.85 (2H, m); 3.40 (2H, m); 3.82 and 3.84 (3H, 2s);5.08-5.13 (2H); 6.85-7.00 (4H, m); 7.36 (1H, m), 7.62 (1H, m); 7.98 (1H,m); 8.10 (1H, m).

Working in a similar way, the following compounds were prepared:

Ethyl1,4-dihydro-6-methyl-2-(N-benzoyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylatehydrochloride

Mass spectrum (chemical ionization, negative ions, ammonium hydroxide):m/e 745 (M+1)⁻ ; 727; 374; 342.

¹ H-NMR (free base) (300 MHz, CDCl₃): delta (ppm): 0.9-1.3 (12H); 1.6(3H, bs); 3.25 (2H, m); 3.82 and 3.83 (3H, 2s); 5.10-5.50 (3H);(6.80-7.00 (4H, m).

Ethyl1,4-dihydro-6-methyl-2-N-(1-oxo-2-methylpropyl)-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylatehydrochloride

Mass spectrum (chemical ionization, positive ions, isobutane): m/e 711(M+1)⁺ ; 460; 321; 238.

¹ HNMR (free base) (300 MHz, CDCl₃): delta (ppm): 0.96-1.25 (18H);2.24-2.32 (3H, 3s); 3.10 (1H, m); 3.38 (2H, m); 3.81 and 3.83 (3H, 2s);5.08-5.16 (3H); 6.90 (4H, m); 7.35 (1H, m); 7.60 (1H, bd); 7.98 (1H, m);8.10 (1H, bs).

Ethyl1,4-dihydro-6-methyl-2-(N-ethoxycarbonyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylatehydrochloride

Mass spectrum (chemical ionization, negative ions, ammonium hydroxide):m/e 711 (M-1)⁻ ; 666; 342.

¹ HNMR (free base) (300 MHz, CDCl₃): delta (ppm): 1.10-1.30 (15H);2.28-2.40 (3H, m); 2.80 (2H, m); 3.35 (2H, m); 3.82 and 3.84 (3H, 2s);5.10 (1H, d); 6.90 (4H, m); 7.35 (1H, bt); 7.62 (1H, bd); 7.98 (1H, bd);8.11 (1H, m).

Ethyl1,4-dihydro-6-methyl-2-(N-methylsulfonyl-N-(2-(2-hydroxy-3-(2-methoxyphenoxy)-propylamino)-2-methylpropyl)-aminomethyl)-4-(3-nitrophenyl)-3,5-pyridinedicarboxylatehydrochloride

Mass spectrum (chemical ionization, negative ions, isobutane): m/e 718(M)⁻ ; 639; 372; 345.

¹ H-NMR (free base) (300 MHz, CDCl₃); delta (ppm): 1.15-1.25 (12H); 2.38and 2.40 (3H, 2s); 2.80 (2H, m); 3.00 (3H, bs); 3.19 (2H, m); 3.83 and3.84 (3H, 2s); 4.56 (1H, dd); 4.88 (1H, d); 5.10 (1H, d); 6.90 (4H; 7.37(1H, t); 7.66 (1H, bd); 7.98 (1H, bd); 8.12 (1H, bs).

EXAMPLE 16 Evaluation of the Pharmacological Activity in vitro

Calcium-antagonist activity of the compounds of formula I has beentested as capability of antagonizing the effect of Ca⁺⁺ submaximalconcentrations (3 mM) on preparations of rabbit mesenteric artery inKrebs depolarizer, prepared according to Towart "J. Cardiovasc.Pharmacol. 4, 895, (1982)".

The compounds of this invention, tested as calcium antagonist agents onthe rabbit mesenteric artery show an IC₅₀ of from 10 to 200 (nM); Kiaffinity for beta₁ receptors is of from 30 to 2000 (nM) and for beta₂receptors is of from 20 to 5000 (nM).

By way of example, IC₅₀ of some compounds of formula I are given in thefollowing table 1.

                  TABLE 1                                                         ______________________________________                                        rabbit mesenteric artery test                                                 Compound        IC.sub.50 (nM)                                                ______________________________________                                        Compound 1      47                                                            diastereoisomer A                                                                             15                                                            diastereoisomer B                                                                             120                                                           ______________________________________                                    

Moreover, the beta-blocking activity has been tested by means of thebinding test both towards beta₁ heart receptors and towards beta₂ lungreceptor in mouse according to the methods described in the J. Biol.Chem., 253, 5090, (1978) and in the Br. J. Pharmacol., 68, 57, (1980).

The compounds of formula I showed a greater affinity towards beta₁receptors than towards beta₂ receptors.

By way of example, in table 2 the receptorial affinity data as Ki (nM)for some compounds of formula I are given.

                  TABLE 2                                                         ______________________________________                                        Receptorial affinity                                                                           Ki (nM)  Ki (nM)                                                              rat      rat                                                                  heart    Lung                                                                 beta.sub.1                                                                             beta.sub.2                                          Compound         receptors                                                                              receptors                                           ______________________________________                                        diastereoisomer A                                                                              600       2050                                               diastereoisomer B                                                                              165       560                                                atenolol         840      18000                                               ______________________________________                                    

Pharmacological Activity in vivo

The compounds of formula I produce antihypertensive effects in rat anddog with concomitant reduction of the heart rate.

For example, in the anesthetized dog, compound 1 caused a heart ratereduction of from 9 to 23% and a reduction of the mean arterial pressureof from 3 to 15% at doses of from 100 to 400 ug/kg; at the same dosesdiastereoisomer A caused a heart rate reduction of from 17 to 30% and amean arterial pressure reduction of from 12 to 25%, respectively. Bothhypotensive effect and bradycardia proved to be particularly durable,lasting over five hours.

We claim:
 1. A compound of the formula ##STR15## wherein Ar is anoptionally substituted mono- or dicyclo aromatic or heteroaromatic ringsystem, having at most 10 ring atoms, any heteroaromatic ring having atleast 5 ring atoms, any substituent of a substituted ring system being amember selected from the group consisting of halogen, hydroxy, C₁ -C₅alkyl, C₂ -C₅ alkenyl, C₁ -C₃ alkoxy, allyloxy, alkoxyalkyl having from1 to 5 carbon atoms in each of the alkyl and alkoxy moieties andoptional unsaturation in the chain, phenoxy, phenylalkoxy,aminocarbonylalkyl having from 1 to 3 carbon atoms in the alkyl moiety,cyano, carboxy, carbamoylalkyl, aminocarboxy, amino, mono-alkylamino anddialkylamino wherein the nitrogen atom is optionally a ring member;eachof R and R₁ is, independently, hydrogen or C₁ -C₃ alkyl; R₂ is astraight-chain or branched unsubstituted or aryl-substituted C₁ -C₇alkyl, straight-chain or branched unsubstituted or aryl-substituted C₂-C₇ alkenyl, or X--R₇, where X is CO, CS or SO₂, and R₇ is alkyl oralkoxyalkyl having from 1 to 5 carbon atoms in each of the alkyl andalkoxy moieties, hydroxy, C₁ -C₃ alkoxy, phenyl, mono-alkylamino ordi-alkylamino having from 1 to 5 carbon atoms in each alkyl moiety or C₁-C₅ alkylthio; R₃ is cyano, amino or optionally-fluoro-substituted C₁-C₃ alkyl; each of R₄ and R₆ is, independently, alkyl or alkoxyalkylhaving from 1 to 5 carbon atoms in each alkyl and alkoxy moiety; R₅ isan optionally-substituted ring selected from the group consisting ofphenyl, napthyl, tetrahydronaphthyl and indanyl, wherein any ringsubstituent is a member selected from the group consisting of halogen,hydroxy, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, alkanoyl,trifluoromethyl, amino, nitro, carbamoyl, cyano, alkylthio,carbamoylalkyl and alkanoylamino having up to six carbon atoms in thealkyl moiety; each of m and n is, independently, 1, 2 or 3; or a saltthereof with an organic or inorganic pharmaceutically-acceptable acid.2. A compound according to claim 1, wherein Ar is anoptionally-substituted monocyclic or bicyclic ring selected from thegroup consisting of phenyl, naphthyl, isobenzofuranyl, benzofuranyl,3,4-dihydrocarbostyryl, benzopyranyl, tetrahydronaphthyl, carbazolyl,indenyl, indolyl and 1,2,5-thiadiazolyl, and any ring substituent is amember selected from the group consisting of fluorine, chlorine,bromine, acetyl, allyl, carbamoylmethyl, butyroylamino, cyclohexyl,cyano, hydroxy, butyroyl, acetylamino, methoxycarbonyl, methoxyethyl,methoxy, allyloxy, cyclopentyl, cyclopropyl, morpholine, ethyl andisobutyroyl.
 3. A compound according to claim 1, whereinAr is a memberselected from the group consisting of 2-methoxyphenyl, 2-allyloxyphenyl,2-cyanophenyl, 2-methylphenyl, 2-allylphenyl, 4-carbamoylmethylphenyl,4-hydroxyphenyl, 4-morpholino-1,2,5-thiadiazol-3-yl,indol-4-yl and3,4-dihydro-1(H)-carbostyryl-5-yl; each of R and R₁ is, independently,hydrogen or methyl; R₂ has its previously-ascribed meaning; R₃ is methylor trifluoromethyl; R₅ is substituted phenyl, any substituent of whichis a member selected from the group consisting of nitro, trifluoromethyland halogen; X is a carbonyl or sulfonic group; and R₇ is methyl, ethyl,isopropyl, phenyl, dimethylamino, diethylamino, methoxy or ethoxy.
 4. Acompound of claim 1 wherein R₃ is cyano.
 5. A compound of claim 1wherein R₃ is amino.
 6. A compound of claim 1 wherein R₃ is C₁ -C₃alkyl.
 7. A compound of claim 1 wherein R₃ is fluoro-substituted C₁ -C₃alkyl.
 8. A compound of the formula ##STR16## wherein Ar is a memberselected from the group consisting of phenyl, naphthyl, isobenzofuranyl,benzofuranyl, 3,4-dihydrocarbostyryl, benzopyranyl, tetrahydronaphthyl,carbazolyl, indenyl, indolyl and 1,2,5-thiadiazolyl optionallysubstituted by fluorine, chlorine, bromine, acetyl, allyl,carbamoylmethyl, butyroylamino, cyclohexyl, cyano, hydroxy, butyroyl,acetylamino, methoxycarbonyl, methoxyethyl, methoxy, allyloxy,cyclopentyl, cyclopropyl, morpholine, ethyl or isobutyroyl;each of R andR₁ is, independently, hydrogen or C₁ -C₃ alkyl; R₂ isoptionally-aryl-substituted straight or branched C₁ -C₇ alkyl,optionally-aryl-substituted straight or branched C₂ -C₇ alkenyl, orX--R₇, where X is CO, CS or SO₂, and R₇ is alkyl or alkoxyalkyl havingfrom 1 to 5 carbon atoms in each alkyl and alkoxy moiety, hydroxy, C₁--C₃ alkoxy, mono- or di-alkylamino having from 1 to 5 carbon atoms ineach alkyl moiety, or C₁ -C₅ alkylthio; R₃ is cyano, amino oroptionally-fluoro-substituted C₁ -C₃ alkyl; each of R₄ and R₆ is,independently, alkyl or alkoxyalkyl having from 1 to 5 carbon atoms ineach of the alkyl and alkoxy moieties; R₅ is optionally-ring-substitutedphenyl, naphthyl, tetrahydronaphthyl or indanyl, wherein any ringsubstituent is a member selected from the group consisting of halogen,hydroxy, alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkyl, alkanoyl,trifluoromethyl, amino, nitro, carbamoyl, cyano, alkylthio,carbamoylalkyl and alkanoylamino having up to 6 carbon atoms in thealkyl moiety; each of m and n is, independently, 1, 2 or 3; or a saltthereof with an organic or inorganic pharmaceutically-acceptable acid.9. A compound according to claim 1, whereinAr is a member selected fromthe group consisting of 2-methoxyphenyl, 2-allyloxyphenyl,2-cyanophenyl, 2-methylphenyl, 2-allylphenyl, 4-carbamoylmethylphenyl,4-hydroxyphenyl, 4-morpholino-1,2,5-thiadiazol-3-yl, indol-4-yl and3,4-dihydro-1(H)-carbostyryl-5-yl; each of R and R₁ is, independently,hydrogen or methyl; R₂ is optionally-aryl-substituted straight orbranched C₁ -C₇ alkyl, optionally-aryl-substituted straight or branchedC₂ -C₇ alkenyl, or X--R₇, where X is a carbonyl or a sulfonic group, andR₇ is methyl, ethyl, isopropyl, phenyl, dimethylamino, diethylamino,methoxy or ethoxy; R₃ is methyl or trifluoromethyl; and R₅ is asubstituted phenyl where any substituent is a member selected from thegroup consisting of nitro, trifluoromethyl and halogen.
 10. A compoundof claim 8 wherein R₃ is cyano.
 11. A compound of claim 8 wherein R₃ isamino.
 12. A compound of claim 8 wherein R₃ is C₁ -C₃ alkyl.
 13. Acompound of claim 8 wherein R₃ is fluoro-substituted C₁ -C₃ alkyl.
 14. Acompound of claim 1 whereinAr is a member selected from the groupconsisting of 2-methoxyphenyl, 2-allyloxyphenyl, 2-cyanophenyl,2-methylphenyl, 2-allylphenyl, 4-carbamoylmethylphenyl, 4-hydroxyphenyl,4-morpholino-1,2,5-thiadiazol-3-yl, indol-4-yl and3,4-dihydro-2(H)-carbostyryl-5-yl; each of R and R₁ is, independently,hydrogen or C₁ -C₃ alkyl; R₂ is optionally-aryl-substituted straight orbranched C₁ -C₇ alkyl, optionally-aryl-substituted straight or branchedC₂ -C₇ alkenyl, or X--R₇, where X is CO, CS or SO₂, and R₇ is alkyl oralkoxyalkyl having from 1 to 5 carbon atoms in each of the alkyl andalkoxy moieties, hydroxy, C₁ -C₃ alkoxy, monoalkylamino or dialkylaminohaving from 1 to 5 carbon atoms in each alkyl moiety, or C₁ -C₅alkylthio; R₃ is cyano, amino or optionally-fluoro-substituted C₁ -C₃alkyl; each of R₄ and R₆ is, independently, alkyl or alkoxyalkyl havingfrom 1 to 5 carbon atoms in each alkyl and alkoxy moiety; R₅ isoptionally-substituted ring selected from the group consisting ofphenyl, naphthyl, tetrahydronaphthyl and indanyl, wherein anysubstituent of a substituted ring is a member selected from the groupconsisting of halogen, hydroxy, alkyl, alkenyl, alkoxy, alkenyloxy,alkoxyalkyl, alkanoyl, trifluoromethyl, amino, nitro, carbamoyl, cyano,alkylthio, carbamoylalkyl and alkanoylamino having up to 6 carbon atomsin the alkyl moiety; each of m and n is, independently, 1, 2 or 3; or asalt thereof with an organic or inorganic pharmaceutically-acceptableacid.
 15. A compound of claim 14, whereineach of R and R₁ is,independently, hydrogen or methyl; R₂ is optionally-aryl-substitutedstraight or branched C₁ -C₇ alkyl, optionally-aryl-substituted straightor branched C₂ -C₇ alkenyl, or X--R₇, where X is a carbonyl or asulfonic group, and R₇ is methyl, ethyl, isopropyl, phenyl,dimethylamino, diethylamino, methoxy or ethoxy; R₃ is methyl ortrifluoromethyl; and R₅ is phenyl optionally substituted by nitro,trifluoromethyl or halogen.
 16. A pharmaceutical composition useful fortreating vasospastic, angina, hypertension and vasoconstrictionpathologies, containing an effective amount of a compound of claim 1together with a pharmaceutical excipient.
 17. A pharmaceuticalcomposition useful for treating vasospastic, angina, hypertension andvasoconstriction pathologies, containing an effective amount of acompound of claim 8 together with a pharmaceutical excipient.
 18. Apharmaceutical composition useful for treating vasospastic, angina,hypertension and vasoconstriction pathologies, containing an effectiveamount of a compound of claim 14 together with a pharmaceuticalexcipient.
 19. A compound of claim 1 wherein Ar is anoptionally-substituted member selected from the group consisting ofphenyl, naphthyl, isobenzofuranyl, benzofuranyl, 3,4-dihydrocarbostyryl,benzopyranyl, tetrahydronaphthyl, carbazolyl, indenyl, indolyl and1,2,5-thiadazolyl.